To carefully examine changes in the composition of the intestinal mucosal immune system over time in SIV-infected macaques we have examined lymphocyte subsets in both mucosal inductive and effector sites. Lymphocytes were examined for CD2, CD3, CD4, CD8, CD20, CD25 and gamma delta TCR expression. For control comparisons, 6 uninfected animals were examined and it was determined that the composition of the normal rhesus intestinal mucosal immune system is similar to that reported in humans. Gamma delta T cell expression was also characterized in the macaque species for the first time, demonstrating that their expression in the macaque intestine is proportionally similar to those of humans. SIV infected animals examined thus far were inoculated with SIVmac239/YE, SIVmac239/316Em*, and SIVmac239 nef-delete and tested at postinoculation intervals of 7, 14, 21, and 50 days. These studies have demonstrated marked differences in the immunophenotypic composition of intestinal lymphocytes from macaques infected with various strains of SIV at different postinoculation intervals. Rapid and profound depletions of CD4+ lymphocytes were detected in the intestine of animals inoculated with pathogenic strains of SIV (SIVmac239YE and SIVmac239/316Em*), whereas CD4:CD8 ratios remained relatively stable in animals infected with a non-pathogenic strain (SIV nef-delete). Changes in the mesenteric lymph node were less profound, with minimal changes in CD4:CD8 ratios in the acute stage of infection. Furthermore, animals inoculated with SIV nef-delete showed marked increases in T lymphocyte activation as determined by increased CD25 expression, whereas CD25 expression dropped in animals infected with pathogenic strains. These studies have shown that profound differences in lymphocyte composition and activation occur between animals infected with pathogenic strains of SIV compared to a strain that may be considered as a modified live vaccine.